Donor T Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD pathogenesis at Clonal Levels after Bone Marrow Transplantation in mice

The success of allogeneic hematopoietic cell transplantation (allo-HCT) is undermined by the development of graft-versus-host disease (GVHD). Using next-generation sequencing of TCRbeta chain locus, we defined the feature of T-cell repertoires in mice after syngeneic or allogeneic bone marrow transplantation. We extensively studied post-transplant T-cell repertoire in multiple lymphoid and non-lymphoid GVHD target organs, including peripheral blood, spleen, peripheral lymph nodes, mesenteric lymph nodes, liver, lungs, gut and skin. Our study provides a spectrum analysis of T-cell repertoire recovery across broad tissue sites. We examined the potential of blood sample as tool to predict the dominant clones in GVHD target organs and detection of de novo generated top clones from pre-transplant donor T cells. Our study highlights the importance of T-cell repertoire profiling in understanding the biology of allogeneic T-cell response and immune repertoire sequencing-based methods may represent a novel personalized strategy to guide diagnosis and therapy in GVHD.

异基因造血细胞移植（allogeneic hematopoietic cell transplantation, 简称allo-HCT）的临床疗效会因移植物抗宿主病（graft-versus-host disease, 简称GVHD）的发生而受到显著削弱。本研究通过对T细胞受体β链基因座（TCRβ chain locus）开展下一代测序（next-generation sequencing），明确了同基因或异基因骨髓移植后小鼠体内的T细胞受体库特征。我们全面分析了移植后多个GVHD靶器官——包括外周血、脾脏、外周淋巴结、肠系膜淋巴结、肝脏、肺脏、肠道与皮肤——内的淋巴与非淋巴组织中的T细胞受体库动态变化。本研究对跨广泛组织位点的T细胞受体库重建过程开展了全景分析。我们评估了外周血样本作为预测GVHD靶器官优势克隆、以及检测移植前供者T细胞新生产生的优势克隆的工具的潜力。本研究强调了T细胞受体库谱分析在解析异基因T细胞应答生物学机制中的重要意义，基于免疫受体库测序的技术方法有望成为指导GVHD诊断与治疗的新型个性化策略。